Comparing the Dosing Period in Package Inserts of Antimicrobial Agents Between Japan and the United States

Introduction: The duration of antimicrobial therapy is a critical evaluation index of antimicrobial stewardship (AS). The inclusion of the dosing period on package inserts provides a strong reason for clinical intervention by pharmacists in cases where physicians prescribe inappropriate dosing periods. This study investigated differences in the description of dosing periods in antimicrobial package inserts between Japan and the U.S. Methods: We conducted a survey comparing differences in the dosing period of oral and injectable antimicrobials approved and marketed in Japan and the U.S. as of May 1, 2021. The Fisher exact test was used to compare the presence or absence of a description of the dosing period on the package insert between these two countries. Results: We evaluated 69 antimicrobial agents, of which 34 were oral; and 35 were injectable agents. In Japan, 20 (29.0%) of the antimicrobials had package inserts stating the dosing periods, compared with 58 (84.1%) in the U.S. (p < 0.001). Conclusions: It was found that the information on the duration of administration was missing from the package insert in Japan compared to the U.S. Lack of information on the duration of administration may lead to long-term administration by the treating physician and also make it difficult for the pharmacist to inquire about the administration. It is expected that the inclusion of scientifically-based dosing periods in all package inserts will promote AS among physicians and pharmacists who are not specialists in infectious disease therapy.


Introduction
Worldwide measures to prepare for the threat of drug-resistant bacteria are being implemented based on the WHO's Global Action Plan [1]. In Japan, since 2016, measures against drug-resistant bacteria have been taken in six areas by the National Action Plan on Antimicrobial Resistance (AMR). The outcome indices for these measures are the proportion of specified antimicrobial-resistant bacteria and the use of antimicrobials [2]. The aims of antimicrobial stewardship (AS) are to determine indications for antimicrobials and optimal antimicrobial regimens to improve patients' outcomes and minimize the adverse events caused by antimicrobial use [3].
In Japan, the package insert was established by Articles 52, 54, and 68-2 of the Act on Securing Quality, Efficacy, and Safety of Products, Including Pharmaceuticals and Medical Devices (commonly known as the Pharmaceutical and Medical Device [PMD] Act]) [4]. Among the many sources of drug information, the package insert is the only document established by law that is attached to any drug. Based on the order of the Ministry of Health, Labour, and Welfare (MHLW) [5], the PMD Act states that dose, administration, and other necessary care for the use and handling of information are required. While there is no regulation for treatment duration on package insert under the PMD Act. As a result, information on the dosing period is not always included in the package inserts of antimicrobial agents in Japan, and physicians like to administer longer durations than generally recommended [6].
In the U.S., Federal Regulation Section 201.100 (Prescription of drugs for human use) stipulates the package insert must include information about the indications, effects, dose, routes, methods, frequency, and dosing period. Additionally, Federal Regulation Section 314.50 (content and format of a new drug application) 1 2 1 1 1 1 states a proposed package insert must be submitted for new drug applications. In the Japanese antimicrobial stewardship guidelines, it was suggested that the preceding U.S. practices be investigated, and we considered a comparison between the U.S. and Japan [7]. So far, there are limited reports comparing the dosing period stated in antimicrobial package inserts between Japan and the U.S. from the perspective of AS. We considered that the difference in the description of the treatment duration in the package insert might affect the appropriate use of antimicrobial agents and investigated the difference in the description of the dosing period in the package insert.

Analyzed antimicrobial agents
We investigated medical antimicrobial agents for oral and injectable use that were approved and marketed in both Japan and the U.S. as of May 1, 2021. We extracted the data for Japan using the drug database published on the Health Insurance Claims Review and Reimbursement Services website [8]. We obtained the package inserts of the antimicrobial agents in Japan from the Pharmaceuticals and Medical Devices Agency website [9] and those in the U.S. from the Drugs@FDA [10] or DailyMed websites [11]. In cases where both original and generic versions of the same drug were available, we used the package insert of the original drug for our survey. We excluded antimicrobials from our study if an agent with the same ingredients was not approved and marketed in the U.S. or if the antimicrobial did not include bacterial infections as one of its indications for use. Only the adult formulation was included if oral medications included both an adult and a pediatric formulation. If there were multiple forms of an oral drug with the same ingredients, only one form was included in the dosage, and administration was the same (in order of priority: tablets, capsules, dispersions, and liquids). If there were multiple indications, the duration of administration was considered to be stated if it was stated for at least one of the indications.

Statistical analysis
We compared the presence or absence of a description of the dosing period on the package insert between Japan and the U.S. using the Fisher exact test. A two-tailed p-value of < 0.05 was considered statistically significant. All statistical analyses were performed using JMP Pro v15 software (SAS Institute Japan, Tokyo, Japan).

Results
Of the 69 antimicrobial agents that were approved and marketed in both Japan and the U.S. as of May 1, 2021, 34 were oral, and 35 were injectable drugs. Among the oral antimicrobials, nine (26.5%) were antituberculous agents ( Figure 1, Table 1, and Table 2). β-lactams accounted for 14 (40.0%) of the injectable drugs.   Comparisons of all antimicrobial agents (oral and injectable) revealed that 20 (29.0%) and 58 (84.1%) of the drug products included in this study listed the dosing period in the package insert in Japan and the U.S., respectively (p < 0.001). In a comparison of oral antimicrobials only, 14 (41.2%) and 29 (85.3%) of the drug products included in this study listed the dosing period in Japan and the U.S., respectively (p < 0.001). A comparison of the injectable antimicrobials only revealed that six (17.1%) and 29 (82.9%) of the drug products included in this study listed the dosing period in Japan and the U.S., respectively (p < 0.001) ( Table 3).

FIGURE 1: Antimicrobial agents included and excluded in our study
The indications and the dosing period indicated on the package inserts for the antimicrobial agents are in Table 4 (Japan) and Table 5 (the U.S.).

Japan
The U.S.

P-value
Oral and injectable antimicrobial agents (n=69)

Discussion
Our study is the first report focusing on the absence of information on the dosing period in the package inserts in Japan and comparing the package inserts of the antimicrobial agents in Japan and the U.S. optimizing the dosing period is a critical issue in promoting AS. Our findings showed that the rate of inclusion of the dosing period in the package inserts of antimicrobial agents in Japan was <50% of that of the U.S. Especially the description of the dosing period for infections such as pneumonia and urinary tract infections was low ( Table 4). In contrast, there were frequent descriptions of the dosing period for pneumonia and urinary tract infections in the package inserts for the U.S. antimicrobials ( Table 5). For example, in the U.S., the package insert for levofloxacin (LVFX) includes descriptions of the dosing period for 12 types of infections. We also found that not all indications are listed in the Japanese package insert ( Table  4). It is suggested to list clinical indications for reference by clinicians. Although there are guidelines on infectious disease treatment, the package inserts are attached to all products and are highly accessible. Practical information included in the package inserts may assist the treating physicians in administering antibiotics.
The package insert is the document pharmacists most often refer to when questioning doctors about prescriptions [12]. A questionnaire survey about AS administered to Japanese pharmacists reported that 72.7% of them had been aware of inappropriate antimicrobial use, but only 28.5% had intervened [13].
In the same survey, only 25.1% of pharmacists could collect sufficient information about AS for prescription questions [14]. The lack of information on the dosing period in the package inserts of antimicrobial agents may make it difficult for pharmacists to intervene in cases of the inappropriate duration of antimicrobial therapy. The lack of a dosing period in the package inserts of antimicrobials in Japan may affect the physician's consideration of the duration of antimicrobial therapy. A questionnaire survey reported that 20% of Japanese hospital doctors administer antimicrobials without criteria for the dosing period [14]. It is crucial to ensure appropriate dosing periods by combining prospective audit and feedback, education, and the development of regional and facility-specific guidelines, as well as revising information in package inserts [15]. Enhancing the description of the dosing period in the package inserts is helpful for pharmacists and physicians who are not specialists in administering antibiotics with the correct dosing period. One of the actions of the National Action Plan on AMR is to review the information included in package inserts (e.g., precautions for use) for antimicrobials based on scientific evidence [2].
In Japan, there are no reports of extensive surveys on the appropriateness of antimicrobial drug administration, including the dosing period. Multiple interventions are performed simultaneously in many cases of AS, making it difficult to assess the impact of specific interventions [16]. Thus, assessing the outcome of including the dosing period in the antimicrobial package inserts is challenging. However, the package insert is supposed to promote the appropriateness of antimicrobial administration. Kimura et al. reported that physicians in Japan treat patients with Clostridioides difficile infection using metronidazole (median: 10 days, interquartile range: 7-13 days) [17], and the dosing period for enteritis is listed as 10-14 days in the package insert in Japan. The result suggested that including the dosing period in this package, insert may contribute to treatment at the appropriate dosing period.
Our study had several limitations. First, although we surveyed oral and injectable antimicrobial agents approved and marketed in Japan and the U.S., the indications for antimicrobial agents in the two countries may differ. It should also be noted that no comparisons were made with European countries. Our survey did not compare or evaluate the dosing period listed in the package inserts of antimicrobial agents with the duration recommended in guidelines for various infectious diseases. There are also differences between Japan and the U.S. in dosage. For example, the maximum daily dosage of levofloxacin differs between the US and Japan (750 mg and 500 mg). Although this study focused on the duration of administration, the dosage should also be considered. In addition, how the inclusion of package inserts affects pharmacist intervention and the reduction in prescribing time for physicians was not analyzed in this study. The impact of modifying the package inserts also needs to be analyzed.

Conclusions
As a conclusion, there was an absence of dosing period information in the package inserts in Japan compared with the U.S. The description of a scientifically based dosing period in the package inserts of antimicrobials in Japan is expected to promote AS among physicians and pharmacists who are not specialists in infectious disease therapy.

Additional Information Disclosures
Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.